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Abstract

Fibroblasts in the tumor stroma are well recognized as having an indispensable role in carcinogenesis, including in the initiation of epithelial tumor formation. The association between cancer cells and fibroblasts has been highlighted in several previous studies. Regulation factors released from cancer‑associated fibroblasts (CAFs) into the tumor microenvironment have essential roles, including the support of tumor growth, angiogenesis, metastasis and therapy resistance. A mutual interaction between tumor‑induced fibroblast activation, and fibroblast‑induced tumor proliferation and metastasis occurs, thus CAFs act as tumor supporters. Previous studies have reported that by developing fibroblast‑targeting drugs, it may be possible to interrupt the interaction between fibroblasts and the tumor, thus resulting in the suppression of tumor growth, and metastasis. The present review focused on the reciprocal feedback loop between fibroblasts and cancer cells, and evaluated the potential application of anti‑CAF agents in the treatment of cancer.

Introduction

Tumors that comprise a mass of malignant epithelial
cells are also surrounded by multiple non-cancerous cell
populations, including fibroblasts, endothelial cells, pericytes,
immune regulatory cells and cytokines in the extracellular matrix
(ECM) (1). These stromal cells
surrounding the tumor form a distinct microenvironment and were not
considered to possess a role in cancer progression. However, it
became evident that the molecular and biological abnormalities of
cancer cells could not fully explain the complex changes involved
in the regulation of tumor progression (2). Thus, an increasing number of studies
have focused on the functions of the tumor microenvironment in
cancer progression (3–5).

Activated fibroblasts, termed cancer-associated
fibroblasts (CAFs), are one of the major components of stromal
cells. CAFs were first identified as negative factors in tumor
development that had no effect on tumor cells; however, they have
been identified as an essential component in tumor progression
(6). With the reciprocal crosstalk
between cancer cells and fibroblasts, CAFs undergo various
morphological and biological transitions in response to tumor
progression (7). Furthermore, CAFs
have an important role in maintaining an optimal microenvironment
for cancer cell survival and proliferation (6,7). Studies
investigating the role of CAFs have reported that the therapeutic
targeting of cancer cells alone is insufficient for the treatment
of cancer (8). Thus, cancer therapy
should co-target cancer cells and their microenvironment. CAFs are
essential components to the tumor microenvironment and therefore
represent a molecular target for the treatment of cancer (9).

The present study is a review of the recent
developments in CAF research, and is aimed at gaining an improved
understanding of the biological mechanisms underlying CAF
involvement in tumor progression. Furthermore, the association
between cancer cells and the tumor microenvironment was analyzed in
order to identify novel strategies for the treatment of cancer.

General characteristics of CAFs

CAFs are a heterogeneous population of cells with
various origins, the majority of which are derived from resident
fibroblasts. CAFs may also be derived from other cells, including
mesenchymal stem cells (MSCs), epithelial, pericytes, adipocytes
and endothelial cells (10). CAFs in
the tumor stroma can be differentiated according to their
morphology and specific identifiable markers. CAFs are generally
presented as large spindle-shaped cells similar to smooth muscle
cells (myofilaments and electron dense patches) (11). α-smooth muscle actin is regarded as
the most widely used biomarker for identifying CAFs (12). Fibroblast activation protein α (FAPα)
is a cytomembrane protein that is selectively expressed by
activated CAFs in various types of human epithelial cancer
(13). Furthermore, podoplanin-a,
S100A4, vimentin, fibroblast specific protein-1 (FSP-1), and
platelet-derived growth factor (PDGF) receptors α and β are
expressed in CAFs (14). Insulin-like
growth factor-binding protein 7 (IGFBP7), a novel biomarker for
tumor fibroblasts in epithelial cancer, has also been detected in
CAFs through genetic screenings and immunohistochemical studies.
IGFBP7-expressing CAFs have been demonstrated to promote colon
cancer cell proliferation through paracrine tumor-stroma
interactions in vitro (15).

The application of microarray gene-expression
analysis has enabled the comprehensive characterization of CAFs and
has increased awareness on the importance of CAFs in oncological
studies. A total of 46 differentially expressed genes regulated by
the transforming growth factor (TGF)-β signaling pathway were
identified in 15 paired CAF and normal fibroblast (NF) cell lines
(16). All 46 genes were identified
to encode for paracrine factors that are released into the tumor
microenvironment. Of these results, 11 genes
[intercellular-adhesion molecule 1 (ICAM1), THBS2, MME, OXTR,
PDE3B, B3GALT2, EVI2B, COL14A1, GAL and MCTP2] were used to form a
prognostic signature of CAFs in non-small cell lung cancer (NSCLC)
(16). Similar studies have
identified differentially-expressed genes between CAFs and NFs
(17–20). Integrin α11 was identified to be
primarily expressed in CAFs and possess prognostic significance for
NSCLC (17). Furthermore,
cyclooxygenase 2 and TGF-β2 expression in CAFs was confirmed
through immunohistochemical analysis in metastatic colon cancer
(18). In human primary pancreatic
adenocarcinoma, smoothened homolog was identified to be
overexpressed in CAFs compared with the expression in pancreatic
NFs (19). In addition, numerous
altered gene transcripts have been identified in breast CAFs,
including that of ribsosomal protein S6 kinase α3, fibroblastic
growth factor (FGF) receptor 1, nardilysin that enhances shedding
of EGF (NRD1), cyclin-dependent kinase inhibitor 1B, NFY and
prostaglandin E synthase 2 (20).
However, no significant differences in the gene expression pattern
of NFs were reported with the most upregulated gene being chromobox
2, a polycomb homolog repressor of proto oncogenes (20).

Tumors induce fibroblast activation

When cancer cells metastasize to another organ, they
recruit NFs to the tumor mass. The activated phenotype of
fibroblasts in the tumor mass are induced by different genetic and
epigenetic changes that are self-regulated, and regulated by cancer
cells; however, the mechanisms underlying the transformation of NFs
to CAFs remains unclear (21).

MicroRNAs (miRNAs/miRs) are an abundant type of
endogenous small RNA molecule that downregulate target gene
expression (24). A previous study
demonstrated that miR-155 is upregulated, whereas miR-31 and
miR-214 are downregulated in ovarian CAFs (25). C-C motif chemokine ligand (CCL) 5 was
identified as a target gene of miR-214. The results demonstrated
that ovarian cancer cells induce the transformation of NFs to CAFs
partially through regulation by miRNAs when NFs are co-cultured
with cancer cells (25). These
findings suggest that miRNAs have a regulatory role in the
transformation of NFs to CAFs. Other miRNAs that have been
identified to be differentially expressed in CAFs are listed in
Table I (26–30).

CAFs induce tumor growth

Tumor growth depends on the abnormal and
uncontrollable proliferation of cancer cells with simultaneous
changes to the microenvironment. Among the stromal cells in the
microenvironment surrounding the tumor, increasing evidence has
reported that CAFs are targets and inducers of tumorigenic
activation signals (31,32).

CAFs produce autocrine and/or paracrine cytokines
that promote the biological characteristics of tumors. In addition
to classical growth factors, including EGF and hepatocyte growth
factor (HGF), novel CAF-secreted proteins [secreted frizzled
related protein 1, and IGF like family member (IGF) 1 and 2], and
membrane molecules (integrin α11 and syndecan-1) have also been
identified to possess cancer cell-supporting roles (33). These factors directly or indirectly
stimulate tumor growth and survival, or enhance their migratory and
invasive properties.

Previous studies have demonstrated that chemokines
secreted by CAFs into the microenvironment allow for the
recruitment of bone marrow-derived cells (BMCs) and immune cells
(34). CXCL12 (35), CXCL14 (36) and CCL5 (37) have been identified as pro-metastatic
factors. In addition, MSC-derived CAFs are recruited to the stroma
of the dysplastic stomach, and express interleukin (IL)-6, Wnt
family member (Wnt) 5α and bone morphogenetic protein 4, all of
which promote tumor growth through DNA hypomethylation (38). Furthermore, MSC-derived CAFs are
recruited to the tumor through TGF-β and CXCL12 signaling (38). In oral squamous cell carcinoma (OCC),
CCL2 expression in CAFs is upregulated, promoting the production of
endogenous reactive oxygen species (ROS) in OC cells (OCCs)
(37). Consequently, ROS induces the
expression of cell cycle regulatory proteins in OCCs, and promotes
OCC proliferation, migration and invasion (39). Together, these chemokines and
cytokines create a suitable microenvironment allowing for the
proliferation and metastasis of cancer cells.

CAFs stimulate tumor angiogenesis

Vascular endothelial growth factor (VEGF) was
originally identified as a multifunctional cytokine in angiogenesis
and lymphangiogenesis (40). The
interaction between tumor and stromal cells can result in increased
VEGF expression, with CAFs being the primary source of VEGF
(41). Furthermore, CAF-derived PDGF
has been demonstrated to be an essential factor in activating VEGF
production. PDGF/PDGF receptor (R) signaling is an important
regulatory pathway primarily involved in angiogenesis (41). PDGFs indirectly promote angiogenesis
by recruiting stromal fibroblasts that secrete VEGF (42). Furthermore, PDGFs are able to recruit
and induce BMCs to form endothelial or smooth muscle cells.
Subsequently, PDGFs promote the proliferation and migration of
endothelial, and smooth muscle cells (42). PDGF subunit B, which is produced by
endothelial cells can induce the migration of pericytes to the
vessel wall and maintain endothelial stability, thus leading to
tumor angiogenesis (43).

Nagasaki et al (44) reported that cancer cells stimulate the
secretion of IL-6 from fibroblasts, subsequently inducing tumor
angiogenesis. IL-6R neutralization antibody inhibited IL-6
signaling and tumor angiogenesis by inhibiting the interaction
between the cancer, and stroma. This finding suggests that IL-6 is
a novel target for anti-angiogenesis therapy (44).

CAFs mediate tumor metastasis

Increasing evidence suggests a metastatic support
role of CAFs in tumors (45,46), whereas data regarding the presence and
role of CAFs in lymph node and distant metastasis is deficient.
Stromal reactions in metastatic lymph nodes, possibly comprising
metastasis-associated fibroblasts, have been described as reactive
and fibrotic tissue with enhanced deposition of vitronectin and
fibronectin, desmoplasia, nodal fibrosis and hyaline stroma
(47). Immunohistochemical
characterization of CAFs was reported in one of these studies,
which assessed metastatic lymph node tissue from a patient with
uterine cervix adenocarcinoma who received preoperative
chemotherapy (47). Certain studies
have suggested that the mesenchymal-like phenotype of CAFs is
involved in enhancing the metastasis of cancer cells, whereas NFs
with the epithelial-like phenotype inhibit the migration of breast
cancer cells (48). Similarly, normal
prostate epithelial cells induce intraepithelial neoplasia in
vivo when co-injected with CAFs, but not when co-injected with
NFs (49).

Notably, CAFs in the stroma of triple-negative
breast cancer samples have been demonstrated to select for bone
metastatic cells (52). CAFs produce
CXCL12 and IGF1, which are prognostic markers for bone relapse and
activators of the phosphatidylinositol 3-kinase (PI3K)/AKT
serine/threonine kinase (AKT) signaling pathway (52). Cancer cells are primed for metastasis
in the CXCL12-rich microenvironment of the bone marrow, thus
suggesting an important role of CAFs in tumor metastasis. Another
study demonstrated that a reduction in miR-148a expression in CAFs
results in increased Wnt activity through the upregulation of its
target gene WNT10B. Consequently, increased Wnt activity results in
increased migration of endometrial cancer cells (53).

A study reported that the downregulation of miR-26b
in CAFs stimulates the migration of fibroblasts, which is a
dominant characteristic of the CAF phenotype. Furthermore, CAFs
with reduced expression of miR-26b promote the migration and
invasion of human breast cancer cells (54). Additionally, the PTEN/miR-320/ETS2
axis secretes proteins, such as Emilin2, that distinguish between
normal and malignant stroma, and is associated with a higher rate
of relapse in patients with breast cancer (55). This demonstrates that miR-320 is an
essential regulator of the signaling pathway in fibroblasts
involved in the regulation of the tumor microenvironment. Similar
to in breast cancer, in prostate cancer, the downregulation of
miR-15 and −16 in CAFs is mediated through activation of the AKT,
and extracellular signal-regulated kinase signaling pathways,
promoting prostate cancer migration, and angiogenesis (56).

CAFs induce resistance of cancer cells
to therapy

Compared with cancer cells, CAFs are relatively
genetically stable with a reduced probability of developing
drug-resistance, thus representing as a potential therapeutic
target with lower chances for the development of chemoresistance
(57,58). However, an increasing amount of data
has suggested that fibroblasts have a protective role that allows
cancer cells to evade therapy, as described below.

PDGF

The interstitial fluid pressure (IFP) in the center
of solid tumors is increased compared with that in the surrounding
tumor tissue (59). Higher IFP
reduces the efficiency of drug penetration into the tumor tissue,
thus reducing the concentration of the drug reaching the tumor
cells and increasing tumor cell viability (58). Strategies on improving chemotherapy
have focused on reducing tumor IFP in order to increase the
efficiency of drug transport and penetration into tumors (60).

HGF

HGF has been identified as an essential factor in of
CAF-mediated resistance to B-Raf proto-oncogene serine/threonine
kinase (BRAF) inhibitor therapy in melanoma with
BRAFV600E mutation, as well as lapatinib resistance in
HER2+ breast cancer (63,64).

TKIs exhibit strong inhibitory effects against NSCLC
with epidermal growth factor receptor (EGFR)-activating mutations
(65). However, the possibility of
intrinsic or developing acquired resistance is an important
consideration in the management of patients with cancer. The
overexpression of HGF in CAF, a ligand of HGF receptor (MET), has
been reported to contribute to resistance to EGFR-TKIs (66).

EGFR and HGF are coexpressed in colorectal cancer
(CRC) cell lines, and the activation of both receptors
synergistically induces the proliferation of cancer cells (67). Cetuximab suppresses cell growth
through dephosphorylation of EGFR, mitogen-activated protein kinase
(MAPK), and/or the AKT signaling pathway (68). It was demonstrated that CAF-derived
HGF phosphorylates MET, but not EGFR or receptor tyrosine-protein
kinase erbB-3 in cetuximab-treated cells. Subsequently, this was
revealed to restore cell proliferation and rescue cells from
G1 phase arrest, and apoptosis through restimulation of
the MAPK and AKT signaling pathways (68). Notably, this effect is inhibited by
suppressing MET activation with PHA-665752, a highly specific MET
kinase inhibitor, or by knocking down MET expression using RNA
interference (69).

Together, these data demonstrate that the presence
of fibroblasts secreting HGF confers resistance to therapy. In
addition, HGF can activate MET, which is expressed on
cancer-initiating cells (CICs) in colon cancer, through paracrine
signaling (70). This can sustain
typical CIC properties, including long-term self-renewal,
ultimately leading to resistance to anti-EGFR therapy (70).

Chemokines

Increasing evidence supports the presence of stromal
cytokines that are important in the development of tumor
chemoresistance.

CCL2 is an inflammatory chemokine, which is
recruited by immune cells into the tumor microenvironment and has
been demonstrated to confer resistance to paclitaxel, and docetaxel
in prostate cancer (71). A previous
study demonstrated that CCL2 expression is higher in three
different paclitaxel-resistant ovarian cancer cell lines ES-2/TP,
MES-OV/TP and OVCAR-3/TP compared with parental cells (72). Furthermore, treatment with a CCL2
inhibitor enhances the antitumor efficacy of paclitaxel and
carboplatin combination therapy in ovarian cancer (72). CAFs can induce CCL2 production through
signal transducer and activator of transcription 3 (STAT3)
phosphorylation, and in turn, CAF-derived CCL2 promotes cancer
progression by regulating cancer stem cells through activation of
the Notch signaling pathway (73).

The chemokine CXCL12 is the sole ligand of CXCR4.
CAFs are an important source of CXCL12 in the tumor stroma.
Previous studies have indicated that CXCL12/CXCR4 signaling
contributes to chemoresistance by inducing the activation of focal
adhesion kinase, ERK and AKT signaling pathways, enhancing the
transcriptional activities of β-catenin, and NF-κB, and the
expression of survival proteins (74,75).
Disruption of the CXCR4/CXCL12 signaling pathway has been
demonstrated to sensitize prostate cancer cells to docetaxel
(76). Similar results have been
observed in colon (77) and lung
(78) cancer. Therefore, these
studies suggest that chemokines, including CXCL12, may act as
promising targets for cancer therapy, alone and/or in combination
with other cytotoxic drugs.

Interleukin family

Emerging evidence suggests that the dynamic
crosstalk between tumor cells and stromal fibroblasts underlie drug
resistance. In CRC, IL-17A, which is overexpressed by CAFs in
response to chemotherapy, bind to the IL-17A receptor expressed on
CICs (79). Consequently, this
results in the maintenance and development of therapeutic
resistance of CICs through the upregulation of NF-κB (79). In ER-negative and triple-negative
breast cancer, IL-17A protects from docetaxel-induced cell death
through activation of ERK1, and 2, thus participating in
therapy-resistance development (80).

Other factors

WNT16B is an important fibroblast-derived protein
and treatment-induced factor that confers chemotherapy resistance.
The chemotherapy resistance effects of fibroblast-derived WNT16B
have been detected in vivo and in vitro, indicating
that WNT16B reduces apoptosis induced by chemotherapy drugs in
prostatic carcinoma (85). This study
guides novel directions for combination therapies, including
targeting fibroblast-derived WNT16B, which may reverse
chemoresistance in breast and prostate cancer (85). Fibroblast-secreted high mobility group
protein B1 is released into the tumor microenvironment and performs
paracrine signaling on neighboring cancer cells, which has been
suggested to induce chemoresistance in breast cancer (86).

Interaction loop

A bi-directional activation between cancer cells and
fibroblasts has been identified as the leading cause of formation
of the malignant phenotype of cancer. As aforementioned, the
crosstalk between the two is important for tumor progression, and
the interactions between them are induced by the reciprocal
signaling of secreted components, including cytokines, and
regulatory factors in the ECM. Cullen et al (87) reported that cancer cells produce PDGF,
which induces fibroblast proliferation and the expression of IGF I,
and II. Notably, IGFs secreted by fibroblasts in turn induce cancer
cell proliferation and the synthesis of PDGF (87).

Cancer cells induce the production of matrix
metalloproteinases (MMPs) by fibroblasts, which results in
degradation of the extracellular matrix and enhances the
invasiveness of cancer cells (88).
In return, fibroblasts secrete growth factors, including HGF
(89), keratinocyte growth factor
(90), and IGF-1 and −2 (91), which stimulate the proliferation of
cancer cells. Furthermore, a previous study reported that local
cell-cell interactions between breast cancer cells and fibroblasts
exhibit various effects on numerous genes, including the regulation
of the expression of TGF-β-altered genes (92).

These signaling pathways are involved in positive
feedback loops, which result in increased tumor cell numbers and/or
amplification of signaling molecules, and consequently tumor
therapy resistance. Thus, understanding the biological mechanism
underlying CAFs may aid in the development of novel
molecular-targeted therapies to inhibit these signaling feedback
loops (Fig. 1).

Inhibition of the feedback loop as an
approach for anti-cancer therapy

In order to target CAFs, a possible approach is to
inhibit the feedback loop between fibroblasts and cancer cells.
Such therapies have not yet been applied clinically, but based on
the aforementioned evidence, the potential benefits of these
treatments have been demonstrated. Inhibiting the feedback loop may
involve the following approaches: Inhibition of fibroblasts
directly and disruption of CAF-associated paracrine growth factor
signals (Fig. 2) (6).

Targeting fibroblast markers
directly

Therapy directed at specific fibroblast markers or
the antigens presented on CAFs make CAFs particularly sensitive to
cancer treatment. FAP is a membrane protein that is exclusively
overexpressed on CAFs (93). FAP has
been shown to support tumor growth and proliferation, making it a
potential target for novel anticancer therapies (94). FAP-specific molecules selectively
target fibroblasts and finally inhibit the growth of surrounding
cancer cells (94,95).

FAPα-specific monoclonal antibodies have
demonstrated therapeutic potential in cancer treatment. FAP5-DM1, a
monoclonal maytansinoid-conjugated antibody, was demonstrated to
inhibit and cause the complete regression of tumor growth in
xenograft models of lung, pancreatic, and head and neck cancer
in vivo (96).

Inhibition of FAPα enzyme activity using specific
inhibitors has also been considered a promising approach to
targeting fibroblasts. Using the peptidase inhibitor, PT-100
(talabostat) was revealed to reduce the tumor growth rate in
numerous types of tumor animal models (97). Knocking down FAPα expression resulted
in distinct tumor growth regression in an
LSL-K-rasG12D genetic mouse model of lung cancer
and in a colon cancer model, suggesting a tumor-supporting role of
endogenous FAPα (98). Furthermore,
treatment with PT-630 was able to inhibit tumor growth in the lung
and colon cancer models (98).

Targeting paracrine signaling of
fibroblasts

PDGF/PDGFR signaling pathway

Cancers stimulate CAFs through the activation of
PDGFR. A previous study demonstrated that following the
overexpression of PDGF in cancer cells, there was an increase in
the fibrotic stroma response, thus suggesting an essential role of
PDGFR signaling in fibroblast activation (99).

Multiple TKIs, including imatinib, sorafenib and
sunitinib, confer anti-PDGFR activity, and the association between
TKIs and PDGFR activity is currently being investigated (100). Imatinib, is a breakpoint cluster
region-ABL proto-oncogene 1 non-receptor tyrosine kinase inhibitor,
which also exhibits anti-PDGFR and anti-c-kit kinase activity,
resulting in decreased proliferation, and protein expression
regulation in human colorectal fibroblasts (101). Furthermore, targeting PDGFRs
increases the uptake and therefore the inhibitory effect of
chemotherapeutics, including paclitaxel, by decreasing the IFP
(62).

The indolinone derivative BIBF1120 is a potent
inhibitor of VEGFR, PDGFR and FGFR family members. It has been
revealed to inhibit MAPK and Akt signaling pathways in endothelial
cells, pericytes, and smooth muscle cells, all of which contribute
to angiogenesis, thus resulting in the inhibition of cancer cell
proliferation and apoptosis. BIBF1120 has been applied clinically
for the treatment of several types of tumor (102). Taken together, these findings
suggest that the inhibition of PDGFR signaling may serve as a novel
treatment approach for cancer.

HGF/MET signaling pathway

HGF is a growth factor that is primarily secreted by
fibroblasts to activate c-Met on cancer cells (103). Genetic and biological studies have
suggested that HGF and its receptor MET are potential targets for
cancer treatment. The progress in understanding the structure and
function of HGF/MET has led to the development of targeting drugs
and numerous small molecule MET kinase inhibitors. Reports from
previous clinical trails demonstrated that inhibiting MET signaling
has great therapeutic value in several types of human cancers,
including NSCLC (104,105).

The use of the anti-HGF monoclonal antibodies
AMG-102 (rilotumumab) and AV-299 (ficlatuzumab) has been
investigated in previous clinical trials (106,107).
Furthermore, the anti-MET agents represent a novel strategy for the
inhibition of the MET signaling pathway. Several phase I and II
clinical trials have investigated the use of novel small molecules
that target MET tyrosine kinase, including tivantinib (108), cabozantinib (109) and crizotinib (110–112).
With the results of these translational and clinical studies,
HGF/MET-targeted therapy is becoming a promising therapeutic choice
for patients with NSCLC.

MMPs/MMP inhibitors (MMPIs)

MMPs are primarily derived from CAFs in various
types of tumor. MMPs have been extensively detected in animal model
experiments, which have demonstrated the importance of these
proteases in inducing tumor growth, metastasis and angiogenesis
(113,114). Inhibitors can be used to
therapeutically target MMPs and lower the enzymatic activity,
providing a prospective for future studies. Even though the
majority of clinical trials on these drugs have reported
insufficient results, research on MMPIs remains ongoing (115,116).
Considering these explanations, one of the major difficulties in
the future is the development of inhibitors or antibodies that bind
to the active site of the enzyme and are highly specific to certain
MMPs (117).

TGF-β signaling

TGF-β stimulates myofibroblast differentiation and
the inhibition of TGF-β signaling in stromal fibroblasts result in
significant regression in tumor growth; however, the antitumor
effects of TGF-β signaling may depend primarily on individual tumor
models (118). The TGF-β signaling
pathway is increasingly considered as a therapeutic target due to
its role in cancer cells and its capacity to instruct a
protumorigenic program in tumor stromal cells (119). Several therapeutic agents that
inhibit the TGF-β signaling pathway have been studied in
preclinical and clinical trials. Neutralizing antibodies, soluble
receptors and antisense oligonucleotides that target the
ligand-receptor interaction, and inhibit the function of TGFBRI or
TGFBRII have been studied in clinical experiments (120). The clinical application of the
TGFBRI kinase inhibitor LY2157299 has been investigated in
glioblastoma (121), hepatocellular
carcinoma (122) and advanced
pancreatic cancer (123); these
studies have provided promising results.

Crosstalk between cancer cells and CAFs through
TGF-β could suggest another therapeutic target. IL-11 has been
recognized for its capacity to promote the maturation of platelets
producing megakaryocyte progenitors in vitro and in the bone
marrow in vivo (124). A
previous study investigated the pro-metastatic effect of IL-11,
which is secreted by TGF-β-stimulated CAFs in CRC (125). It was reported that IL-11 promotes
the survival of tumor cells at the sites of metastatic colonization
(125). This finding suggests that
the clinical use of IL-11 to treat thrombocytopenia caused by
chemotherapy agents should be reconsidered and the use of anti-IL11
therapies against CRC should be evaluated.

Conclusion

CAFs are considered as an essential component of
tumorigenesis. Increasing evidence has suggested that CAFs exhibit
a positive effect on the development of solid tumors. CAFs can
modulate tumor microenvironment through diverse mechanisms, thus
supporting tumor progression. Pre-clinical and clinical trials have
revealed that CAFs are a potential target for the treatment of
solid tumors.